Regeneration of bone for fracture repair, alveolar ridge augmentation, dental implants and craniofacial surgery relies on the recruitment of osteoblast precursors to the site. The body does not possess a large population of such osteoblast precursors, but recruit stem cells with the ability to undergo differentiation upon demand. The stromal component of bone marrow contains a major reservoir of such mesenchymal stem cells (MSC), which can be induced to differentiate into osteoblasts. Whether such cells remain as uncommitted stem cells, or become committed to a particular differentiation pathway, is under the control of both systemic and local factors. One set of local factors, the bone morphogenetic proteins (BMPs), has attracted considerable interest as candidate therapies for promoting bone formation. Most BMPs are effective in promoting increased bone formation in several animal models. They are, therefore, promising candidates for inducing new bone formation in humans. However, evidence for their effectiveness in human trials is not impressive, and we currently have little understanding of BMPs in adult human bone formation. The Principal Investigator has recently analyzed MSC cultures from adult bone marrow for their ability to respond to BMP-2 and glucocorticoids. Human MSC readily undergo osteogenesis with glucocorticoids, but not BMP. Furthermore, in contrast to rat and mouse stem cells and mature human osteoblasts, MSC from human marrow lack ALK-6, a receptor utilized by BMP-2 and BMP-4 and implicated in bone formation. The proposed research is intended to define the role of BMPs and their receptors during adult bone formation by addressing the following questions: 1) Do human MSC need ALK-6 for osteogenesis or can they utilize other BMP receptors? Can they respond to any BMPs? 2) Is human MSC osteogenesis regulated by inhibitors of BMP signaling? 3) Do human osteoprogenitors develop BMP-responsiveness during osteoblast differentiation? These studies will not only define the capacity of BMPs to promote bone formation in human MSC, but will also characterize the role of BMP signaling components in MSC osteogenesis. By doing so, it is hoped to provide guidance for future clinical approaches using mesenchymal stem cells in bone repair and formation.